Effects of the ligand linkers on stability of mixed-valence Cu(I)Cu(II) and catalytic aerobic alcohol oxidation activity

We synthesized a class of ligands that feature single (L1) and dual amine-bis(triazole) chelates (L2 with a 1,3-phenylene linker and L3 with a 1,5-naphthalene linker). Our findings which were derived from UV–Vis titrations, crystal structure analysis of relevant copper complexes, and DFT calculations indicate the formation of both mononuclear CuBr(L1) and dinuclear (μ-Ln)(CuBr)2 (Ln = L2 and L3) complexes. The catalytic activities of CuBr/Ln, in combination with TEMPO (2,2,6,6-tetramethylpiperidin-1-yl)oxyl) co-catalyst and NMI (N-methylimidazole) for aerobic alcohol oxidation, reveal the following activity trend: CuBr/L3 > CuBr/L2 > CuBr/L1. Furthermore, electrochemical data from in-situ generated CuBr complexes suggest that the higher catalytic performance of CuBr/L3 is attributed to the presence of less stable mixed-valence and more reducible Cu(I)-L3-Cu(II) species compared to Cu(I)-L2-Cu(II). This difference is a result of weaker σ interactions between Cu–Namine, larger bridging π systems, and a longer Cu···Cu distance in the presence of L3. Additionally, the catalyst system, CuBr/L3/TEMPO/NMI, efficiently promotes the aerobic oxidation of benzyl alcohol to benzaldehyde at room temperature in CH3CN with a high turnover frequency (TOF) of 38 h−1 at 1 h.

high catalytic activities of (L)[Cu(X)(Y)] 2 with the TON value reaching up to 232 (for benzaldehyde) after 20 h at 70 °C were attributed to hydrophobic internal environments surrounding the copper centers, consequently promoting the binding of O 2 and alcohol substrate molecules to the copper active sites.Furthermore, our group has recently shown that catalytic activities of trinuclear copper(II) catalysts supported by bis(triazolyl) ligands [(μ-Br)Cu 3 (btm) 3 (H 2 O)]Br 2 (5 mol% Cu), in the presence of TEMPO (5 mol%) and NMI (10 mol%) in CH 3 CN, toward aerobic oxidation of benzyl alcohol were better than that of the related mononuclear Cu(II) complex containing triazolylphenylmethanol ligands 8 .However, the catalytic performances of these catalysts were moderate with the highest TOF value of 9.8 h −1 for benzaldehyde at room temperature after 3 h.It is possible that structural rigidity around Cu centers of the trinuclear Cu cluster impedes a geometrical rearrangement from pseudo-square pyramidal Cu(II) to tetrahedral Cu(I), a key mechanistic step in the alcohol oxidation catalysis, which leads to slower reactions.
More recently, we have reported exceptional activities of the copper catalyst systems featuring amine-triazole ligands functionalized with poly(ethylene glycol) substituents for aerobic oxidation of activated 1° alcohols to the corresponding aldehydes in water 15 .Given these promising results and the potential oxidation activities exhibited by multinuclear copper catalysts, we developed a class of amine-bis(triazolyl) ligands L1-L3 which possess either a single (L1) and dual copper chelating sites (L2 and L3), as shown in Fig. 2. With L2 and L3 ligands, structures of the multinuclear copper complexes are not rigid and copper centers are expected to electronically interact through the inductive effect and MLCT (i.e., d electrons (Cu) → π* (LUMO) of the ligands) 16 , potentially resulting in improved catalytic oxidation activities.Herein, we aim to assess the effects of aromatic aminetriazole linkers on aerobic alcohol oxidation activities of multinuclear copper catalysts.In particular, the role of

Experimental section Materials
All air-sensitive reactions were carried out in dry glassware with dry solvents under N 2 atmosphere in a glovebox or using standard Schlenk techniques.All reagents including propargyl bromide (> 97% stabilized in MgO) were purchased from TCI and Sigma-Aldrich and used without further purifications.Reagent-grade solvents were purchased from LabScan.Benzyl azide 8 and N,N-dipropargylaniline 17 were prepared following literature methods.
NMR spectra were acquired in deuterated solvents at room temperature using a Bruker-Ascend™ 400 highresolution magnetic resonance spectrometer for 1 H (400 MHz) and 13 C{ 1 H} (100 MHz) nuclei with chemical shifts referenced to residual solvent peaks.Fourier transform-infrared (FT-IR) spectra were collected on a Bruker model Alpha spectrometer from solid samples.Electrospray Ionization mass spectra (ESI-MS) of CH 3 CN solutions of TP2, TP3, L2, and L3 were obtained in positive-ion mode on a Bruker micrOTOF II.Elemental analyses were performed using Perkin Elmer 2400 CHN.A Shimadzu UV-2600 UV-Vis spectrophotometer was used to record the absorption data of aqueous solutions of CuBr/L1-L3 in the range of 200-800 nm.Computational details of CuBr/L1-L3 were described in the Electronic Supporting Information.The Bruker D8 QUEST CMOS PHOTON II diffractometer (λ Mo = 0.71073 Å) was employed to obtain X-ray diffraction data for 1 and 4 at a temperature of 296 K, while the Bruker D8 Venture CMOS PHOTON I diffractometer (λ Cu = 1.54178Å) was utilized at temperatures of 100 K and 296 K for complexes 2 and 3, respectively.Product conversions obtained from catalytic experiments were analyzed by GLC on a 6890N Agilent Technologies gas chromatograph equipped with a 5973N Agilent Technologies quadrupole mass detector with anisole as an internal standard.

Synthesis of tetrapropargyl diamine compounds TP2 and TP3.
The synthesis of TP2 and TP3 follows the literature method for N,N-dipropargylaniline (DP1) 17 with slight modifications.To a mixture of the amine substrate and K 2 CO 3 was added 10 ml of DMF.After stirring until the homogeneous solution was obtained, propargyl bromide was added and the reaction mixture was stirred at room temperature for 2 days.Then, the solution was extracted with 3 × 50 mL CH 2 Cl 2 and the combined filtrate was washed with 3 × 50 mL DI water, followed by 50 mL of saturated brine solution.The CH 2 Cl 2 solution was dried with anhydrous Na 2 SO 4 and all volatiles were removed under vacuum to afford the spectroscopically clean product.

Synthesis of bis-and tetra(triazolyl) ligands L1-L3
The syntheses of L1-L3 follow that of L1 18 with some modifications.Under N 2 , to a mixture of dipropargylamine (for L1) or tetrapropargylamine (for L2 and L3) and PhCH 2 N 3 was added 10 mL of CH 2 Cl 2 followed by NEt 3 .The reaction solution was stirred at room temperature until homogeneous.Then, the reaction flask was wrapped with an aluminum foil before CuI was added.After 24 h, the reaction mixture was stirred with EDTA in 10% aqueous NH 4 OH at room temperature for 8 h, after which the solution was extracted with 3 × 50 mL CH 2 Cl 2 and the organic filtrate was washed with 50 mL of saturated brine solution.The combined organic layers were dried with anhydrous Na 2 SO 4 , filtered, and the solvent was evaporated under vacuum and crystallized in a 1:1 CH 2 Cl 2 /diethyl ether solution to afford the product.

Synthesis of copper(II) nitrate complexes
To a 10 mL CH 2 Cl 2 solution of the triazolyl ligand was added a 10 mL EtOH solution of Cu(NO 3 ) 2 •3H 2 O.The reaction mixture was stirred at room temperature for 24 h, after which all volatiles were removed in vacuo.The product was isolated via crystallization. [

General procedure for alcohol oxidation
The stock solution of the CuBr/Ln (Ln = L1-L3) catalyst was prepared from stirring a mixture of CuBr (7.2 mg, 0.050 mmol) and 1.0 equiv L1 (0.050 mmol) or 2.0 equiv L2, L3 (0.10 mmol) in 5 mL of CH 3 CN at room temperature for 15 min, after which the CH 3 CN solution was filtered.The volume of the resulting filtrate was adjusted to 10.0 mL with CH 3 CN.For a typical catalytic reaction, 1.0 mmol of alcohol was dissolved in the 5.0 mL CH 3 CN stock solution of CuBr/Ln (Ln = L1-L3) followed by an addition of TEMPO (7.9 mg, 0.050 mmol), NMI (8.0 μL, 0.10 mmol), and anisole (10.9 μL, 0.010 mmol).The reaction solution was allowed to stir at room temperature for a given time, after which it was filtered through a short silica column using EtOAc as an eluent.The percentage conversions were determined using GC-MS methods with anisole as an internal standard.
For the reusability study, benzyl alcohol (1.0 mmol) was dissolved in a 10.0 mL CH 3 CN stock solution of CuBr/L3, followed by an addition of TEMPO (7.9 mg, 0.050 mmol) and NMI (8.0 µL, 0.10 mmol).After 2 h, 1.00 mL of the reaction mixture was collected and filtered through a short silica column.A 100 µL aliquot of the filtrate was sampled and diluted to 1.5 mL with EtOAc, to which 0.010 mmol of anisole was added as an internal standard.The percent conversion of the resulting solution was determined via GC-MS.To initiate the subsequent catalytic run, benzyl alcohol (1.0 mmol), TEMPO (0.050 mmol), and NMI (0.10 mmol) were added to the remaining reaction mixture.After another 2 h, the reaction mixture was sampled, filtered, and diluted following the same workup procedure described above.The percent conversions for the five subsequent runs were also determined using GC-MS with anisole as an internal standard.

Synthesis of ligands and copper complexes
The N,N-bis(triazolylmethyl)aniline ligand L1 and the N,N,N',N'-tetra(triazolylmethyl)amine ligands L2 and L3 (Fig. 2) were synthesized using a multi-step process starting with the propargylation of the corresponding aryl amine substrates.Subsequently, the Cu-catalyzed azide-alkyne cycloaddition (CuAAC) between the resulting alkynes and benzyl azide, promoted by CuI/NEt 3 in CH 2 Cl 2 afforded L1 and L2 in 74% and 81% yields, respectively.However, under the same conditions, the yield of the naphthalene-containing ligand L3 was notably lower at 41% (Fig. 3).The reaction of L1, which possesses a single metal binding site, with Cu(NO 3 ) 2 •3H 2 O in a mixture of CH 3 OH/CH 2 Cl 2 solvent led to the formation of the copper(II) complex 1. Single crystals obtained from a layer diffusion of CH 3 OH onto the diethyl ether solution of 1 crystallize in the P1 space group, with the Cu atom occupying the centrosymmetric position.X-ray crystallographic analysis reveals that each asymmetric unit of 1 contains a mononuclear bis-chelate Cu(II) complex, displaying tetragonally distorted octahedral geometry at Cu (Fig. 4a).The complex is accompanied by two outer-sphere NO 3 − counterions and a CH 3 OH molecule.The L1 ligand coordinates to Cu(II) in a tridentate, facial coordination mode.Notably, the Cu-N amine bond (2.722 Å) is significantly longer compared to the Cu-N trz bonds (1.948(2) Å and 2.022(2) Å), as a result of Jahn-Teller distortion.
On the other hand, crystal structures of 2 and 3 reveal one-dimensional polymeric structures, where L2 and L3 ligands act as organic linkers between Cu(II) ions (Fig. 4b,c).The crystal structure of 2 contains bis-chelate Cu(II) ions, which are linked by 1,3-phenylene moieties, and Cu(NO 3 ) 4 2− as the counterions.In the {Cu(L2) 2 } n complexes, each Cu atom is coordinated with two tridentate L2 ligands in a facial coordination mode.Comparable to 1, the Cu-N amine bond of 2 is approximately 0.69 Å longer than the Cu-N trz bonds (2.687 cf.1.970(2) and 2.002(2) Å).However, for 3, due to the more electron delocalized nature of naphthalene, the N amine atom becomes a weaker Lewis base.Consequently, L3 binds to Cu(II) ions in a bidentate fashion with only Cu-N trz coordination present.The solid-state structure of 3 shows distorted octahedral bis-chelate Cu(II) complexes containing two bidentate N trz chelates occupying cis positions (Fig. 4c).In the mean time, k 2 -O,O-NO 3 -serves as an inner-sphere ligand occupying the two remaining coordination sites, while the other NO 3 -ion acts as a counterion to balance the charges.It should be noted that the Cu•••Cu distances separated by aromatic 1,3-phenylene and 1,5-naphthalene linkers are 8.172 Å and 13.970 Å, respectively.
We investigated the structure of CuBr/Ln by mixing CuBr with an equimolar amount of L3 in CH 3 CN at room temperature overnight followed by slow evaporation, which resulted in single crystals of 4 in 14% yield after 4 d.However, crystallographic analysis revealed the dinuclear Cu(II) complexes, as shown in Fig. 5.It is plausible that, under aerobic conditions, Cu(I)/L3 undergoes disproportionation, 19 leading to the formation of Cu(II)/L3 and Cu 0 .Complex 4 is centrosymmetric, where both Cu(II) centers are related by inversion symmetry.The fivecoordinate Cu center assumes a geometry intermediate between a trigonal bipyramid and a square-base pyramid (τ = 0.4), featuring an elongated Cu-N amine bond compared to the average Cu-N trz bond length (2.610(3) vs. 1.958(3)Å).With the tridentate coordination of L3, the Cu•••Cu distance of 10.827 Å is closer than that observed in complex 3 (13.970Å).Drawing from the crystal structure of (μ-L3)(Cu II Br 2 ) 2 , we propose that the in-situ generated Cu I Br complex of L2 and L3 also adopts a comparable dinuclear structure.Our attempts to obtain single crystals from a mixture of CuBr and L1 under similar conditions have not been successful.Consequently, the nature of the CuBr/L1 structure, whether mono-or bis-chelate, remains uncertain.
To further elucidate the structures of Cu I Br complexes of L1 and L3, computational studies were carried out using ωB97XD 20 functional and def2-SVP 21 basis set for geometry optimizations and using ωB97XD/def2-TZVPP Figure 3. Synthetic pathway of L3.
The stoichiometric ratios between CuBr and L1-L3 were also determined via UV-vis spectrophotometric titrations.For these measurements, DMSO was selected as the solvent due to better solubility of CuBr/Ln complexes (Ln = L2 and L3) in DMSO compared to CH 3 CN.Absorption data at wavelengths 260, 255, and 258 nm were collected and analyzed using the BindFit program [22][23][24] to obtain the binding constant(s) for the CuBr complexes of L1, L2, and L3, respectively.The analyses suggest stoichiometric ratios of CuBr:Ln as 1:1 for L1, and 2:1 for CuBr:L2 and CuBr:L3, leading to the determination of the binding constants (K) as shown in Table 1.Unsurprisingly, the ligand L3, which possesses a more electron-delocalized naphthalene-based framework, exhibited the weakest binding strength with CuBr, most likely a result of weak Cu-N amine interactions in DMSO.By integrating information from crystal structures, computational study, and UV-vis titrations, proposed structures for CuBr/Ln are illustrated in Fig. 7.

Catalytic aerobic alcohol oxidation activities
The impact of ligands with single and dual metal binding sites on catalytic alcohol oxidation activities were investigated using benzyl alcohol as the model substrate.We observed that the isolated Cu(II) complex 3 (2.5 mol%) from a reaction between Cu(NO 3 ) 2 and L3, combined with TEMPO (5 mol%) and NMI (10 mol%), exhibited low catalytic activities towards aerobic oxidation of benzyl alcohol in CH 3 CN at room temperature, leading to 70% conversion to benzaldehyde at 24 h (entry 1, Table 2).In contrast, in-situ generated CuBr complexes of L1-L3 were more active catalysts and promoted complete oxidation to benzaldehyde at 2 h, under the same conditions (entries 2-4).The ligand L3, which features two copper binding sites and a naphthalene linker, afforded the most active copper catalyst system with 71% conversion of benzyl alcohol at 0.5 h (TOF = 57 h −1 ), followed by L2 (58%) and L1 (32%), respectively.It should be noted that a mixture of CuBr:L3 resulted in a small amount of insoluble, off-white solids, which were filtered out to maintain a homogeneous catalyst system.We characterized  www.nature.com/scientificreports/ the insoluble white solids by 1 H NMR, FT-IR, and ESI-MS, which revealed the presence of the ligand L3, which has low solubility in CH 3 CN, along with a trace amount of CuBr (Figs.S21-S23).The catalytic reaction utilized 2.5 mol% CuBr with 2.5 mol% L1 (1:1 ratio of CuBr:L1) or 1.25 mol% L2 and L3 (2:1 ratio of CuBr:L2 and L3).Notably, changing the CuBr:L3 ratio from 2:1 to 1:1 had no discernible effect on catalytic activity as both ratios provided similar conversions of benzyl alcohol to benzaldehyde after 1 h.Decreasing the amount of CuBr/L3 to 1.0 mol% resulted in 49% conversion of benzyl alcohol to benzaldehyde after 2 h (entry 5, Table 2).In the absence of Ln, the CuBr catalyst stabilized by NMI showed moderate activity, leading to a 63% conversion at 1 h (TOF = 25 h −1 , entry 6).On the other hand, without CuBr, the ligand L3 alone did not exhibit catalytic oxidation activity at 2 h under the same conditions (entry 7).Meanwhile, the well-known catalyst system CuBr/bpy (bpy = 2,2′-bipyridine), generated from a 1:1 mixture of CuBr:bpy, resulted in 51% Table 2. Catalyst comparison for aerobic alcohol oxidation a,b a Reaction conditions: benzyl alcohol (1.0 mmol), CuBr (0.025 mmol), Ln (0.025 or 0.0125 mmol), TEMPO (0.050 mmol), NMI (0.10 mmol) in CH 3 CN (5 ml) under aerobic conditions with 0.010 mmol of anisole as an internal standard, room temperature.b % conversion determined by GC-MS, average of at least two runs.c % Selectivity > 99%.d TOF (h −1 ) = [% conversion/(mol% Cu × time)].e L3 (0.0125 mmol).f CuBr (0.025 mmol), bpy (0.025 mmol).www.nature.com/scientificreports/conversion of benzyl alcohol after 0.5 h (TOF = 41 h −1 , entry 8).Based on catalytic studies, the activity for Cucatalyzed aerobic oxidation of benzyl alcohol follows this trend: L3 > L2 ~ bpy > L1 > no ligand, as illustrated in the reactivity profile (Fig. 8).Furthermore, replacing CuBr/L3 with CuBr 2 /L3 led to only 4% conversion at 2 h although complete aerobic oxidation of benzyl alcohol was achieved within 24 h (entry 9 and Fig. S14).Reusability study of the CuBr/L3 catalyst was also conducted where each catalytic run involved the addition of benzyl alcohol substrate, 5 mol% TEMPO, and 10 mol% NMI at the onset.After 2 h, the catalyst maintained excellent conversions (> 98%) for at least 6 reaction cycles without any loss in catalytic performance.

Entry
The aerobic oxidation activity of the dinuclear catalyst CuBr/L3 was also compared to those of other multinuclear copper-based catalysts previously reported in the literatures, as shown in Table 3.For aerobic oxidation of benzyl alcohol to benzaldehyde, the catalyst CuBr/L3/TEMPO/NMI showed the highest TOF value of 38 h −1 under mild conditions.Given its superior catalytic performance, CuBr/L3 was selected for further substrate scope studies.The catalyst system CuBr/L3/TEMPO/NMI in CH 3 CN exhibited high activity for activated primary alcohols at room temperature, resulting in 72-100% conversions and exclusive formation of the corresponding aldehyde products within 2 h (Table 3).Interestingly, under these conditions, the biomass-derived compound 5-hydroxymethyl-2-furfural (HMF) was also completely oxidized to give exclusively 2,5-diformylfuran (DFF) at

Electrochemical properties
To A = 0.261 V), as displayed in Fig. 9.The additional oxidative process was observed for CuBr/L2 and CuBr/L3 at 0.778 and 0.728 V, respectively (Fig. 9b,c).Upon comparing these oxidative waves with that of the in-situ generated Zn(OTf) 2 /Ln (Ln = L1-L3) complexes under identical conditions, we assigned these peaks to ligand-related oxidation events (Fig. S10).The overlaid CV data comparing the first redox waves of CuBr/Ln, and CuBr/bpy are shown in Fig. 10, showing the first oxidative process of CuBr/Ln to be more positive than that of CuBr/bpy.Furthermore, the reduction potential E pc A , corresponding to the the Scheme 1. Substrate Scope a,b .a Reaction conditions: alcohol substrate (1.0 mmol), CuBr (0.025 mmol), L3 (0.0125 mmol), NMI (0.10 mmol) and TEMPO (0.050 mmol) in MeCN (5 mL) under aerobic conditions at room temperature with 0.010 mmol of anisole as an internal standard.b % conversion based on GC analysis, average of at least two runs.4).This suggests a more facile reduction of the mixed-valence dinuclear copper complexes in the presence of L3.
We further determined the stability of the mixed-valence Cu(I)Cu(II) species and electronic communication (coupling) between copper centers via the comproportionation constants (K c ) for CuBr/L2 and CuBr/L3 calculated using the expression 31 : where ΔE ox is the separation between the two redox potentials for the successive oxidation processes.We found that the K c value of CuBr/L3 is significantly smaller than that of CuBr/L2 (3.54 × 10 3 vs.4.39 × 10 6 , Table 4), suggesting lower stability of the mixed-valence Cu(I)-L3-Cu(II) species and less electronic communication between the copper centers.Less stable Cu(I)-L3-Cu(II) species are also a result of weaker σ interactions between Cu-N amine based on smaller CuBr-L3 binding constants (Table 1), larger bridging π systems, and longer Cu•••Cu distance (i.e., 10.83 Å for 4 cf.8.12 Å for 2).
Based on catalytic results, characterization data, and established mechanisms for mononuclear Cu-catalyzed alcohol oxidation 32,33 , we propose a mechanism for the aerobic alcohol oxidation catalyzed by dinuclear copper catalysts, as shown in Fig. 11.Cycle (1), which involves Cu(I)Cu(I) and Cu(I)Cu(II) species, is believed to be the primary catalytic cycle, as the CuBr-based catalyst system exhibits significantly higher activity than related Cu(II) species (vide supra).Meanwhile, the Cu(II)-Ln-Cu(II) catalyst can also contribute to the catalytic oxidation activity, since the CuBr 2 /L3 catalyst was found to be active, although with much lower oxidation activity (entry 8, Table 2).The higher catalytic performance of CuBr/L3 compared to CuBr/L2 is attributed to the lower stability of the mixed-valence Cu(I)-L3-Cu(II) species I2.This instability is expected to facilitate a more facile reduction from I2 to I1 and the aldehyde product (step iii) consistent with the more positive E pc A value of CuBr/L3 (0.280 V) compared to that of CuBr/L2 (0.045 V), as outlined in Table 4.

Conclusion
In this study, we synthesized a set of of amine-bis(triazole) ligands, containing a single metal binding site L1 and dual metal binding sites L2 and L3 with 1,3-phenylene and 1,5-naphthalene linkers, respectively.Using these ligands, the corresponding mononuclear and multinuclear Cu(II) complexes were successfully generated.X-ray crystallography revealed the formation of one-dimensional coordination polymers and dinuclear Cu(II) complexes with the L2 and L3 ligands.Data obtained from DFT calculations, UV-vis titrations, and the crystal structure of (μ-L3)(CuBr 2 ) 2 supported the proposed formulations of the mononuclear and dinuclear CuBr

Figure 1 .
Figure 1.Examples of multinuclear copper catalysts for aerobic alcohol oxidation.
gain insights into the oxidation activities of these catalyst systems, we investigated the electrochemical properties of the in-situ generated complexes CuBr/Ln (Ln = L1-L3) in CH 3 CN using cyclic voltammetry, with [Bu 4 N]PF 6 as the supporting electrolyte under aerobic conditions.The mononuclear CuBr/L1 exhibited a quasireversible redox wave with an E 1/2 value of 0.053 V vs [Fe(C 5 H 5 ) 2 ] +/0 .On the other hand, the cyclic voltammogram of CuBr/L2 and CuBr/L3 revealed two pairs of redox waves corresponding to the redox processes which are the one-electron oxidation of Cu(I)Cu(I) to Cu(II)Cu(I) (A) and Cu(II)Cu(I) to Cu(II)Cu(II) (B).The first oxidative process of CuBr/L1 and CuBr/L2 are comparable (CuBr/L1: E 1/2 = 0.053 V versus CuBr/L2: E 1/2 A = 0.114 V), while that of CuBr/L3 are more positive (E 1/2
A. b